The urinary tract is normally a sterile environment, kept free of microbes by the flow of urine and by myriad anti-microbial molecules and effector immune cells. However, despite these formidable host defenses and the increasing usage of antibiotics, urinary tract infections (UTIs) remain among the most common of infectious diseases worldwide. Strains of uropathogenic Escherichia coli (UPEC), which are the principal cause of UTIs, are able to invade host bladder epithelial cells and subsequently multiply, forming large intracellular inclusions that resemble biofilms. Alternately, intracellular UPEC can persist at low levels in a more quiescent, non-replicating state that may serve as a reservoir for future recurrent acute infections. Invasion of host cells and tissues within the urinary tract promotes the persistence of UPEC in the face of both innate and adaptive host responses, as well as many antibiotic treatments. The primary objectives of this proposal are to define the host and bacterial factors that mediate UPEC invasion, intracellular growth, and persistence within the bladder epithelium. Biochemical, pharmacological, genetic, and microscopic approaches coupled with in vivo model systems will be employed. It is hoped that the proposed work will provide a more complete understanding of the pathogenesis of both acute and recurrent UTIs and ultimately facilitate the development of improved therapeutics for treating and preventing these exceptionally common infections. PUBLIC HEALTH RELEVANCE: Urinary tract infections are among the most common of infectious diseases, representing a serious economic and medical burden worldwide. By delineating how uropathogenic bacteria colonize and persist within the host, we hope to facilitate the development of improved therapeutics.